Tamoxifen-associated endometrial cancer: key predictors and monitoring

DOI

https://dx.doi.org/10.18565/aig.2026.16

Ivanov I.A., Ermakova E.I., Vislinskaya D.D.
1) Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia; 2) Pavlov First St. Petersburg State Medical University, Ministry of Health of Russia, St. Petersburg, Russia

Tamoxifen is the most common agent for hormone therapy of breast cancer, but its tissue‑specific activity is associated with an increased risk of endometrial cancer. This review systematizes the factors determining individual risk and justifies a differentiated approach to the monitoring of patients with breast cancer. The literature analysis shows that the most significant predictors are the presence of endometrial pathology prior to treatment, the cumulative dose of tamoxifen, overweight, and obesity. A key mechanism underlying the increased risk may be the conversion of tamoxifen tissue activity: in the context of postmenopausal estrogen deficiency, the drug exhibits an agonistic effect on endometrial estrogen receptors, stimulating proliferation; whereas in reproductive‑aged patients its action remains antagonistic. Despite the increased relative risks (RR), the absolute incidence of endometrial cancer remains relatively low, not exceeding 3.1% even after 10 years of therapy.
Conclusion. Identifying high‑risk groups, namely women in peri‑ and postmenopausal periods aged over 50–55 years, those with excess body weight, and those receiving tamoxifen for more than three years, as well as performing ultrasonography prior to treatment enables the management strategies to be optimized. This approach ensures timely diagnosis and minimizes unnecessary invasive procedures, maintaining a balance between oncological vigilance and treatment safety.

Authors’ contributions: Ivanov I.A., Ermakova E.I. – developing the concept of the article; Ivanov I.A., Vislinskaya D.D. – literature review; Ermakova E.I. – editing the article.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The study was conducted without sponsorship.
For citation: Ivanov I.A., Ermakova E.I., Vislinskaya D.D.
Tamoxifen-associated endometrial cancer: key predictors and monitoring.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2026; (4): 52-58 (in Russian)
https://dx.doi.org/10.18565/aig.2026.16

tamoxifen

endometrial cancer

endometrial hyperplasia

breast cancer

postmenopausal period

Full text (in Russian)

Bray F., Ferlay J., Laversanne M., Brewster D.H., Gombe Mbalawa C., Kohler B. et al. Cancer incidence in five continents: inclusion criteria, highlights from volume X and the global status of cancer registration. Int. J. Cancer. 2015; 137(9): 2060-71. https://dx.doi.org/10.1002/ijc.29670
Каприн А.Д., Старинский В.В., Шахзадова А.О., ред. Злокачественные новообразования в России в 2021 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2022. 252 с. [Kaprin A.D., Starinsky V.V., Shakhzadova A.O., eds. Malignant neoplasms in Russia in 2021 (incidence and mortality). Moscow: P.A. Herzen MRIO – branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation; 2022. 252 p. (in Russian)].
Davies C., Godwin J., Gray R., Clarke M., Cutter D. et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011; 378(9793): 771-84. https://dx.doi.org/10.1016/S0140-6736(11)60993-8
Тюляндин С.А., Артамонова Е.В., Жигулев А.Н., Королева И.А., Пароконная А.А., Семиглазова Т.Ю., Стенина М.Б., Фролова М.А. Рак молочной железы. Malignant tumours. 2023; 13(3s2-1): 157-200. [Tyulyandin S.A., Artamonova E.V., Zhigulev A.N., Koroleva I.A., Parokonnaya A.A., Semiglazova T.Yu., Stenina M.B., Frolova M.A. Breast Cancer. Malignant tumours. 2023; 13(3s2-1): 157-200 (in Russian)]. https://dx.doi.org/10.18027/2224-5057-2023-13-3s2-1-157-200
Министерство здравоохранения Российской Федерации. Клинические рекомендации. Рак молочной железы. 2021. [Ministry of Health of the Russian Federation. Clinical guidelines. Breast cancer. 2021 (in Russian)].
Gradishar W.J., Moran M.S., Abraham J., Aft R., Agnese D., Allison K.H. et al. Breast cancer, version 3.2022, NCCN Clinical practice guidelines in oncology. J. Natl. Compr. Canc. Netw. 2022; 20(6): 691-722. https://dx.doi.org/10.6004/jnccn.2022.0030
Гусейнова Р.Г., Ордиянц И.М., Персидская А.А. Клинически значимые факторы риска развития гиперпластических процессов эндометрия у женщин в перименопаузальном возрасте. Акушерство и гинекология. 2021; 8: 32-8. [Huseynova R.G., Ordiyants I.М., Persidskaya A.A. Clinical risk factors for endometrial hyperplastic processes in perimenopausal women. Obstetrics and Gynecology. 2021; (8): 32-8 (in Russian)]. https://dx.doi.org/10.18565/aig.2021.8.32-38
Bernstein L., Deapen D., Cerhan J.R., Schwartz S.M., Liff J., McGann-Maloney E. et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J. Natl. Cancer Inst. 1999; 91(19): 1654-62. https://dx.doi.org/10.1093/jnci/91.19.1654
Ryu K.J., Kim M.S., Lee J.Y., Nam S., Jeong H.G., Kim T. et al. Risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment in premenopausal women with breast cancer. JAMA Netw. Open. 2022; 5(11): e2243951. https://dx.doi.org/10.1001/jamanetworkopen.2022.43951
Committee Opinion No. 601: Tamoxifen and uterine cancer. Obstet. Gynecol. 2014; 123(6): 1394-7. https://dx.doi.org/10.1097/01.AOG.0000450757.18294.cf
Hoogendoorn W.E., Hollema H., van Boven H.H., Bergman E., de Leeuw-Mantel G., Platteel I. et al. Prognosis of uterine corpus cancer after tamoxifen treatment for breast cancer. Breast Cancer Res. Treat. 2008; 112(1): 99-108. https://dx.doi.org/10.1007/s10549-007-9823-1.
Fisher B., Costantino J.P., Redmond C.K., Fisher E.R., Wickerham D.L., Cronin W.M. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J. Natl. Cancer Inst. 1994; 86(7): 527-37. https://dx.doi.org/10.1093/jnci/86.7.527
Ngô C., Brugier C., Plancher C., de la Rochefordière A., Alran S., Féron J.G. et al. Clinico-pathology and prognosis of endometrial cancer in patients previously treated for breast cancer, with or without tamoxifen: a comparative study in 363 patients. Eur. J. Surg. Oncol. 2014; 40(10): 1237-44. https://dx.doi.org/10.1016/j.ejso.2014.05.007
Choi S., Lee Y.J., Jeong J.H., Jung J., Lee J.W., Kim H.J. et al. Risk of endometrial cancer and frequencies of invasive endometrial procedures in young breast cancer survivors treated with tamoxifen: a nationwide study. Front. Oncol. 2021; 11: 636378. https://dx.doi.org/10.3389/fonc.2021.636378
Swerdlow A.J., Jones M.E. Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. J. Natl. Cancer Inst. 2005; 97(5): 375-84. https://dx.doi.org/10.1093/jnci/dji057
Chen J.Y., Kuo S.J., Liaw Y.P., Avital I., Stojadinovic A., Man Y.G. et al. Endometrial cancer incidence in breast cancer patients correlating with age and duration of tamoxifen use: a population based study. J. Cancer. 2014; 5(2): 151-5. https://dx.doi.org/10.7150/jca.8412
Berlière M., Charles A., Galant C., Donnez J. Uterine side effects of tamoxifen: a need for systematic pretreatment screening. Obstet. Gynecol. 1998; 91(1): 40-4. https://dx.doi.org/10.1016/s0029-7844(97)00591-7
Hu R., Hilakivi-Clarke L., Clarke R. Molecular mechanisms of tamoxifen-associated endometrial cancer (review). Oncol. Lett. 2015; 9(4): 1495-501. https://dx.doi.org/10.3892/ol.2015.2962
López D.M.L., Fernández Y.G., Sánchez A.V., Alvarez M.I., Reynaldo M.I.L., Delgado R.C. Baseline hysteroscopic assessment of endometrium in asymptomatic postmenopausal women with estrogen receptor-positive breast cancer. Menopause. 2013; 20(1): 64-71. https://dx.doi.org/10.1097/gme.0b013e318259eaf3
Garuti G., Grossi F., Centinaio G., Sita G., Nalli G., Luerti M. Pretreatment and prospective assessment of endometrium in menopausal women taking tamoxifen for breast cancer. Eur. J. Obstet. Gynecol. Reprod. Biol. 2007; 132(1): 101-6. https://dx.doi.org/10.1016/j.ejogrb.2006.04.001
Stern T., Peleg Hasson S., Saad A., Levanon K., Michaan N., Laskov I. et al. Concomitant diagnosis of endometrial and breast cancer - does the sequence matters? Gynecol. Oncol. Rep. 2021; 38: 100863. https://dx.doi.org/10.1016/j.gore.2021.100863
Matanes E., Volodarsky-Perel A., Eisenberg N., Rottenstreich M., Yasmeen A., Mitric C. et al. Endometrial cancer in germline BRCA mutation carriers: a systematic review and meta-analysis. J. Minim. Invasive Gynecol. 2021; 28(5): 947-56. https://dx.doi.org/10.1016/j.jmig.2020.11.023
Li Z., Wu Q., Song J., Zhang Y., Zhu S., Sun S. Risk of second primary female genital malignancies in women with breast cancer: a SEER analysis. Horm. Cancer. 2018; 9(3): 197-204. https://dx.doi.org/10.1007/s12672-018-0330-0
Bergman L., Beelen M.L., Gallee M.P., Hollema H., Benraadt J., van Leeuwen F.E. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive cancer centres’ ALERT group. Assessment of liver and endometrial cancer risk following tamoxifen. Lancet. 2000; 356(9233): 881-7. https://dx.doi.org/10.1016/s0140-6736(00)02677-5
Ghanavati M., Khorshidi Y., Shadnoush M., Akbari M.E., Ardehali S.H., Chavarri-Guerra Y. et al. Tamoxifen use and risk of endometrial cancer in breast cancer patients: a systematic review and dose-response meta-analysis. Cancer Rep. (Hoboken). 2023; 6(4): e1806. https://dx.doi.org/10.1002/cnr2.1806
Magriples U., Naftolin F., Schwartz P.E., Carcangiu M.L. High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J. Clin. Oncol. 1993; 11(3): 485-90. https://dx.doi.org/10.1200/JCO.1993.11.3.485
Decensi A., Gandini S., Serrano D., Cazzaniga M., Pizzamiglio M., Maffini F. et al. Randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users. J. Clin. Oncol. 2007; 25(27): 4201-9. https://dx.doi.org/10.1200/JCO.2006.09.4318
Fleming C.A., Heneghan H.M., O’Brien D., McCartan D.P., McDermott E.W., Prichard R.S. Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy. Br. J. Surg. 2018; 105(9): 1098-106. https://dx.doi.org/10.1002/bjs.10899
Davies C., Pan H., Godwin J., Gray R., Arriagada R., Raina V. et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013; 381(9869): 805-16. https://dx.doi.org/10.1016/S0140-6736(12)61963-1
Earl H., Gray R., Kerr D., Lee M. The optimal duration of adjuvant tamoxifen treatment for breast cancer remains uncertain: randomize into aTTom. Clin. Oncol. (R. Coll. Radiol.). 1997; 9(3): 141-3. https://dx.doi.org/10.1016/s0936-6555(97)80067-2
Rosell J., Nordenskjöld B., Bengtsson N.-O., Fornander T., Hatschek T., Lindman H. et al. Long-term effects on the incidence of second primary cancers in a randomized trial of two and five years of adjuvant tamoxifen. Acta Oncol. 2017; 56(4): 614-7. https://dx.doi.org/10.1080/0284186X.2016.1273547
Gielen S.C.J.P., Santegoets L.A.M., Hanifi-Moghaddam P., Burger C.W., Blok L.J. Signaling by estrogens and tamoxifen in the human endometrium. J. Steroid Biochem. Mol. Biol. 2008; 109(3-5): 219-23. https://dx.doi.org/10.1016/j.jsbmb.2008.03.021
Ольховская М.А., Сметник А.А. Селективные модуляторы эстрогеновых рецепторов. Акушерство и гинекология. 2011; 6: 31-5. [Olkhovskaya M.A., Smetnik A.A. Selective estrogen receptor modulators. Obstetrics and Gynecology. 2011; (6): 31-5 (in Russian)].
Kurt S., Ozmen S., Yavuz O., Ilgen O., Ulukus E.C. Endometrial pathologies in clinical follow-up of patients with hormone receptor-positive / negative breast cancer. J. Surg. Med. 2023; 7(12): 754-9. https://dx.doi.org/10.28982/josam.7583
Gielen S.C.J.P., Burger C.W., Kühne L.C.M., Hanifi-Moghaddam P., Blok L.J. Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin. J. Soc. Gynecol. Investig. 2005; 12(7): e55-67. https://dx.doi.org/10.1016/j.jsgi.2005.08.003
Gorodeski G.I., Beery R., Lunenfeld B., Geier A. Tamoxifen increases plasma estrogen-binding equivalents and has an estradiol agonistic effect on histologically normal premenopausal and postmenopausal endometrium. Fertil. Steril. 1992; 57(2): 320-7. https://dx.doi.org/10.1016/s0015-0282(16)54838-9
Chu S.C., Hsieh C.J., Wang T.F., Hong M.K., Chu T.Y. Younger tamoxifen-treated breast cancer patients also had higher risk of endometrial cancer and the risk could be reduced by sequenced aromatase inhibitor use: a population-based study in Taiwan. Tzu Chi Med. J. 2019; 32(2): 175-80. https://dx.doi.org/10.4103/tcmj.tcmj_17_19
Fisher B., Costantino J.P., Wickerham D.L., Redmond C.K., Kavanah M., Cronin W.M. et al. Tamoxifen for prevention of breast cancer: report of the National surgical adjuvant breast and bowel project P-1 study. J. Natl. Cancer Inst. 1998; 90(18): 1371-88. https://dx.doi.org/10.1093/jnci/90.18.1371
Shum M.J. Risk factors for endometrial pathology in women with breast cancer and tamoxifen treatment. Hong Kong J. Gynaecol. Obstet. Midwifery. 2022; 22(2): 107-13. https://dx.doi.org/10.12809/hkjgom.22.2.02
Cheng W.F., Lin H.H., Torng P.L., Huang S.C. Comparison of endometrial changes among symptomatic tamoxifen-treated and nontreated premenopausal and postmenopausal breast cancer patients. Gynecol. Oncol. 1997; 66(2): 233-7. https://dx.doi.org/10.1006/gyno.1997.4739
Мамиконян И.О., Саркисов С.Э., Бойко М.А., Гюрджян С.А., Саттаров Ш.Н. Сравнительная оценка методов диагностики состояния эндометрия у пациенток в постменопаузе с раком молочной железы на фоне приема тамоксифена. Акушерство и гинекология. 2013; 10: 59-62. [Mamikonyan I.O., Sarkisov S.E., Boiko M.A., Gyurhyan S.A., Sattarov Sh.N. Comparative assessment of methods for diagnosis of the endometrium in postmenopausal patients with breast cancer taking tamoxifen. Obstetrics and Gynecology. 2013; (10): 59-62 (in Russian)].
Chiofalo B., Mazzon I., Di Angelo Antonio S., Amadore D., Vizza E., Laganà A.S. et al. Hysteroscopic evaluation of endometrial changes in breast cancer women with or without hormone therapies: results from a large multicenter cohort study. J. Minim. Invasive Gynecol. 2020; 27(4): 832-9. https://dx.doi.org/10.1016/j.jmig.2019.08.007
Li W., Chen Q., Xie Y., Hu J., Yang S., Lin M. Prevalence and degree of insulin resistance in Chinese Han women with PCOS: Results from euglycemic-hyperinsulinemic clamps. Clin. Endocrinol. (Oxf). 2019; 90(1): 138-44. https://dx.doi.org/10.1111/cen.13860

Received 19.01.2026

Accepted 25.03.2026

Ilya A. Ivanov PhD, Researcher at the Department of Gynecological Endocrinology, Academician V.I. Kulakov National Medical Research Center for Obstetrics,
Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, +7(962)980-00-18, doctor.i.ivanov@yandex.ru,
https://orcid.org/0000-0003-0751-7566
Elena I. Ermakova, PhD, Senior Researcher at the Department of Gynecological Endocrinology, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, +7(916)848-37-46, e_ermakova@oparina4.ru,
https://orcid.org/0000-0002-6629-051X
Daria D. Vislinskaya, Pavlov First Saint-Petersburg State Medical University, Ministry of Health of Russia, 197022, Russia, St. Petersburg, L’va Tolstogo str., 6-8,
dvislinskaya@list.ru, https://orcid.org/0009-0009-5086-0125
Corresponding author: Ilya A. Ivanov, doctor.i.ivanov@yandex.ru

Tamoxifen-associated endometrial cancer: key predictors and monitoring

Ivanov I.A., Ermakova E.I., Vislinskaya D.D.

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